: The toolbox of synthetic transformations contains a significant gap: there are currently no effective stereoselective methods for preparing alkenyl ether linkages between two structurally complex components. Closing this gap is essential for implementing non-traditional technology for glycoside synthesis, forming an alkenyl ether intermediate linking a carbohydrate alcohol to an acyclic carbohydrate precursor, followed by oxidative oxacyclization onto the alkenyl ether to close the carbohydrate ring, while simultaneously forming the chiral center of the glycoside bond. The long-term goal, beyond this exploratory research (R21) program, is to develop commercially viable syntheses of bioactive oligosaccharides. The overall objective in this application is to establish highly diastereoselective syntheses of glycoside linkages, arising from acyclic polyoxygenated terminal alkynes and sterically hindered cyclic secondary alcohols of protected carbohydrates. The central hypothesis is that the steric hindrance of the electrophilic component in carbon-oxygen bond-forming transformations will be diminished with acyclic sp- or sp2-hybridized electrophiles, relative to the cyclic sp3-hybridized electrophiles in traditional glycosylations. This hypothesis for alkenyl ether synthesis will be tested with a variety of metal-catalyzed processes. The rationale for this research is to expand the rules governing glycoside synthesis, bypassing existing barriers in traditional glycosylation technology arising from steric hindrance and/or lack of stereochemical control. The following specific aims will test the central hypothesis: 1) develop regio- and stereoselective intermolecular hydroalkoxylations of alkynes with carbohydrate alcohols, to form alkenyl ethers in a single step; 2) establish conditions for stereospecific intermolecular transalkenylations with carbohydrate alcohols, to form alkenyl ethers; and 3) identify parameters for stereoselective oxidative oxacyclizations of alkenyl ethers to close glycoside rings. The first aim will test the working hypothesis that vinylidene carbene intermediates with hydrogen bond acceptor ligands will enhance the intermolecular reactivity with alcohols. The second aim will investigate the working hypothesis that increasing electrophilicity of metal catalysts will enhance intermolecular reactivity with alcohols. The third aim will evaluate the working hypothesis that epoxidations directed by hydrogen bonding with allylic oxygen substituents will correspond to the stereochemistry of 1,2-cis-galactosides, especially from cis-alkenyl ethers. The approach is innovative compared with the status quo, as the proposed technology separates the glycosylation process into two distinct stages: first linking two structurally complex reaction partners, and then closing the carbohydrate ring of the glycoside, controlling chiral stereoselectivity by local stereoinduction and mechanism-based stereospecificity. The proposed research is significant, as it creates fundamentally new technology for the chemical synthesis of complex molecules, with applications beyond this program in glycoside synthesis.